All posts by Cort Johnson

The temperature was dropping that December night as I pulled the van into the Ritz Carlton in Incline Village. Sitting about 6500 ft high a couple of miles from Lake Tahoe, I shivered as I remembered the forecast – temperatures in the 20’s with snow on the way. This was not a camping night – tonight I was going to hide out in a hotel.

Weathers’ struggle for survival on Mt Everest has inspired many. His struggle pales, though, compared to what many people with ME/CFS have to endure every day.

Beck Weathers, the speaker at Simmaron Research Foundation’s Donor Appreciation night, probably would have laughed. Weather was there to talk about what his remarkable escape from 29,000 ft. Mt Everest – a gripping survival story which formed the basis for 2015 film Everest – had taught him.

Beck Weathers charged into the Ritz like a storm slamming down the slopes of Everest. It’s been over 20 years since Weathers almost lost his life during the ill-fated Everest expedition that claimed nine lives, but for Weathers, it seemed like it was yesterday as he brought each of us up onto the mountain with him.

Weathers’ wife said Weathers could talk the ears off a rubber rabbit and I believe it. The man is a natural storyteller. Those in the packed ballroom were in for a treat. I don’t know if I’ve ever heard a more evocative story.

Sound effects (wind whirling, ice crunching) were in abundance as Weathers’ voice rose and fell as he brought the fear, the exhaustion, the determination, the beauty, the failures and the triumphs of that expedition to the Simmaron Research Foundation gala dinner. It was an incredible performance.

Multiple operations formed Weathers left had into what he calls his mitt.

The scars were there, too. The missing tip of Weathers’ nose (doctors grew a new one on his forehead) and one missing and another mangled hand demonstrated the price Weathers paid for his time on the mountain.

Weathers was forty-nine at the time, an experienced amateur climber who’d summitted eight major mountains, but nothing left him prepared for what would happen on that May day in 1996. Of all the extraordinary stories to come out of that climb (read “Into Thin Air” and see “Everest“), his was the most remarkable.

Partially blind, Weathers and other climbers were caught by a sudden blizzard in the “Death Zone” above 26,000 feet on the slopes of Mount Everest. In his book, “Left for Dead”, Weathers described what happened.

“Suddenly, the blizzard detonated all around us. It crescendoed into a deafening roar. A thick wall of clouds boiled across the South Col, wrapping us in white, blotting out every discernible feature…It quickly became incredibly cold.”

As the wind suddenly rose to 70 knots and the temperatures dropped to minus 60 degrees Fahrenheit, the group struggled to survive, almost plunging off a 7,000 foot drop. A decision was made that the strongest two would try to make their way to camp. Weathers and others stayed on the Col and huddled together.

That night, a Russian climber took three more of the group down. Weathers and a Japanese climber – each in a hypothermic coma – remained. The next morning, after the storm cleared, a cardiologist determined that Weathers was too close to death to be moved: anyone caught in a hypothermic coma that high on a mountain is going to die. The cardiologist returned to camp alone.

Dead Man Walking

Late that afternoon, however, Weathers woke to see his gray, frozen, gloveless hand. Bouncing it like a block of wood off the ice somehow revived him.

Weathers hadn’t eaten for three days or had any water for two. His oxygen was long gone. By all rights, after lying in a blizzard at 26,000 feet with no sleeping bag or tent, one glove (and one hand and arm) gone, Weathers should have succumbed long ago. He’d already been pronounced and left for dead twice.

But Weathers was alive. Watching the sun begin to set, he estimated he had an hour to find camp or die. It would have been easier to slide into the cozy hypothermic coma he’d been in yesterday. Weathers could feel it tugging at him, but then something got him up and moving.

Oddly enough, it was pictures of his wife and children. Weathers had basically ditched his family in order to climb mountains. His wife was about to divorce him and his relationship with his kids – who rarely saw him – “extremely strained”. Weathers’ obsession with work, fitness and mountaineering had left little time for his family. It was as if they didn’t exist. He could disappear for weeks on an expedition – leaving them fretting – without bothering to contact them.

Yet, as he prepared himself to face a probable death, it wasn’t his work, his many awards, nor his mountain-climbing experiences that came to mind; it was the family he’d left behind.

Weathers was a pathologist with a dark secret. He’d struggled with sometimes severe depression for years. His obsessions with work, fitness and mountain climbing were in some ways simply attempts to escape his depression.

Weathers struggled up, and half-blind, picked a general direction and somehow stumbled, slid, and fell his way into camp where he was put into a tent, shoved into two sleeping bags with hot water bottles – and again pronounced dead. That night, another storm blew up, filled the tent with snow, and blasted Weathers out of his sleeping bag. He was found lying in the snow the next morning.

Weather’s lower right arm and hand were amputated. He asserts that the life-altering realizations that occurred on the Everest climb were worth the physical cost.

The next morning, Weathers was guided by three other climbers down to 20,000 feet, where he was effectively stuck. He was too ill to get further down the mountain and he was still too high for a helicopter rescue. But then, another miracle happened. A daring Pakistani pilot risked his life for a man from another country and religion – and succeeded.

Weathers ended up losing part of his nose, his right hand and lower arm, part of his left hand and several toes to frostbite, but he survived, and he was there to tell the crowd at the Simmaron event that the ordeal was worth it. The loss of his hands, he said, was a small price to pay for getting back his relationship with his family.

What might a story of survival against all odds on the tallest mountain in the world have to say to people with ME/CFS/FM?

Keeping On Keeping on

Weathers never should have woken up. Then partially blind, hypothermic, etc., by all odds he shouldn’t have made it to camp. He had only a vague idea of where it was. Daylight was quickly running out. His eye problems left him slipping, sliding and falling constantly. He’d lost 30 pounds and was at the end of his rope physiologically. He had no roadmap – no decent expectation that he could survive. He simply knew that in order to have a chance of survival, he had to keep walking.

Just as with Weathers, roadmaps for ME/CFS/FM do not exist. Each person’s journey is unique, full of slips and slides, wrong pathways, muddled ideas, mistakes and occasionally victories. All you can do is to be resolved, in the face of everything, to keep “walking”, to keep being informed, to keep participating. Some people do stumble their way into “camp” (health).

The task, though, is far harder for many ME/CFS/FM patients than for Weathers. Beck got off his mountain but many people with ME/CFS and FM, in pain and bed or homebound, live day in and day out, stuck on their own Everests. Beck’s exploits, as inspiring as they are, pale next to the sheer courage and determination it takes many people with ME/CFS/FM for years or even decades – to keep on keeping on.

Just like Beck, without having any idea how they are going to succeed, they keep putting one foot (so to speak) in front of the other.

There’s just no substitute for keeping on. When Weathers got down to 20,000 feet and his wife was told he was still going to die, his wife kept on. Without knowing how she was going to get Weathers off the tallest mountain in the world, she shared his story with everyone she could think of. She told Beck’s story long enough and well enough until it filtered down to one very brave Pakistani pilot.

Through movies, TED talks, videos, blogs and person-to-person interactions, people with ME/CFS are telling their stories – and moving people. There are “helicopter pilots” out there – brave women and men we don’t know about yet (like Pine of the Pineapple Fund) who will be moved to act. All we need to do is keep sharing.

Keeping on – no matter how high the mountain or how treacherous the climb – is the critical element for success.

Conclusion

Weathers’ story was incredibly inspiring. Like many people with ME/CFS/FM, the medical profession gave up on him, and in fact, signed off on his death warrant. Against all odds, though, Weathers was able to survive.

Weathers’ story indicates miracles do happen at times, that serendipity can strike, that helicopters can appear out of the mist at 20,000 feet. Unforeseen discoveries and assistance (the Pineapple Fund’s $5 million donation to the OMF) can happen. We should never discount the possibilities of miracles happening.

Although Weathers got off his mountain, most of us remain on ours. We have our Everests to deal with. Some of Weathers’ realizations while on the mountain could help make our way easier.

There was the critical need to keep putting one foot in front of the other – to stay in the game, so to speak, and not give up even when all is black. Beck shouldn’t have survived, but miracles – unexpected events – showed up. You never know what the future will bring.

There was the need to take responsibility for the mistakes he’d made in his relationships. Finally, there was realization of how empty striving to be a success was for him.

For people with ME/CFS/FM, we can take our own brand of inspiration from Weathers’ survival and his reevaluation of what kept him going on his mountain.

Simmaron gives special thanks to the donor who made Weathers’ talk possible, and to every one of our donors who make our efforts to help get ME/CFS/FM patients off of their mountains possible.

Bruun Wyller continues to surprise. When last heard from this erstwhile cognitive behavioral therapy (CBT) proponent asserted that more research into Epstein-Barr virus in chronic fatigue syndrome (ME/CFS) was needed. Now he’s looking at the interaction between the immune and endocrine systems.

Wyller begins his new study reporting that systemic inflammation is probably present and B-cell functioning is impaired (if modestly) in ME/CFS, but that the picture regarding cytokines is muddier. A meta-analysis of 38 ME/CFS cytokine studies examining 77 cytokines found only one standout – a cytokine called TGF-B. It was consistently elevated in 2/3rds of the studies.

Only one cytokine has more or less consistently shown up elevated in ME/CFS studies – TGF-B

Given its unusual and consistent appearance in cytokine study results, why TGF-B has gotten so little attention in ME/CFS is unclear. The fact that it’s kind of a weird cytokine probably doesn’t help. Secreted by macrophages and some other immune cells, TGF-B can function as both an anti and pro-inflammatory cytokine depending on the situation it’s in.

It’s three forms are involved in a multitude of regulatory processes involving inflammation and immunity. It does more than participate in the immune system; TGF-B also affects or is affected by the two stress response systems in our bodies – the HPA axis and autonomic nervous system. All that makes TGF-B a complex character indeed.

Take our two stress response systems. During stressful situations increased TGF-B levels appear to be associated with increased levels of cortisol – the main stress hormone of the HPA axis. An ME/CFS study examining the gene expression of immune cells found an abnormally high expression of genes that interact with the HPA axis and autonomic nervous system. That suggested that a significant immune-hormone component is present. Indeed, ME/CFS has long been characterized as a neuroendocrineimmune (NEID) – a disease that effects all three systems.

In this study Wyller, a Norwegian researcher, again used his own broad definition of ME/CFS to find patients, but this time he did post hoc analyses using the Fukuda and Canadian Consensus criteria to determine if different definitions of ME/CFS made a difference – they didn’t). As always, Wyller studied adolescents – a lot of them (n=120) and 68 controls to produce a very nice sized study. The data analysis took a long time; the data itself was collected from 2010-2012.

TGF-B actually comes in three forms ((TGF‑β1, TGF‑β2 and TGF‑β3). For the first time ever in ME/CFS Wyller tested for all three forms of TGF-B, as well as norepinephrine, epinephrine and cortisol (urine) and c-reactive protein (serum). He also assessed heart rate variability, and in 29 patients examined their whole blood gene expression. Questionnaires assessing fatigue, inflammatory symptoms, post-exertional malaise, sleep, mood and anxiety were also given.

Results

Wyller expected TGF-B levels to be higher in his adolescent ME/CFS patients, but to his surprise even using the CCC and Fukuda criterias, they were not. Nor was TGF-B associated with any clinical markers such as fatigue, PEM, sleep problems, etc.

Wyller suggests an unusual neuroimmune connection involving TGF-beta and stress hormones such as cortisol (pictured) may be present

The study was looking like a bust until Wyller dug a little deeper. It turned out that TGF-B levels were associated with increased levels of the stress hormones cortisol, norepinephrine and epinephrine in the ME/CFS patients but not in the healthy controls.

An unusual immune-endocrine interaction was occurring in ME/CFS patients that was not found in the healthy controls. For some reason, TGF-B levels rose in conjuction with stress hormones in the ME/CFS patients but not in the healthy controls. All three TGF-B isoform displayed this association.

Plus that association also correlated with symptom severity. Wyller found that the TGF-B-cortisol-autonomic nervous system correlation was strongest in the most fatigued ME/CFS patients. Less fatigued ME/CFS patients, on the other hand, had much less of this association.

Once again, context appeared to be king in the ME/CFS patients. The levels of TGF-B didn’t matter but the network they were embedded in did. A similar scenario showed up in the huge cytokine study conducted by Dr. Montoya and Mark Davis of Stanford. That study, like Wyller’s, didn’t find high levels of cytokines, but it did find that even normal cytokine levels affected symptoms. That suggested some sort of immune hypersensitivity, perhaps associated with some unusual network functioning, was present.

Now Wyller apparently finds an immune and autonomic nervous sensitivity to TGF-B. It’s not the cytokine levels themselves but the effect they have on stress hormones. Indeed, Wyller suggested that the primary disease mechanism in ME/CFS is not altered immune production but altered immune control. Somehow the immune system is affecting other systems in unusual ways.

That’s an intriguing idea given what we’ll shortly see from Dr. Klimas, whose intense testing during exercise suggests that exercise induced immune activity trips off autonomic nervous system problems in ME/CFS. Gordon Broderick’s network studies suggest that cytokine levels don’t need to be high to have untoward effects on ME/CFS patients – they simply have to be embedded in an unusual immune network.

Wyller believes a complex neuro-endocrine-immune interaction may be contributing to the fatigue and possibly the EBV issues in ME/CFS.

Dr. Klimas will be trying in a series of small studies to move those systems back to normal this year. (More on that later.)

Wyller’s findings suggest that his “sustained arousal” hypothesis may be correct and that the “sustained arousal” he believes is present in ME/CFS is being triggered by the immune system. His small gene expression study possibly bares this out. Wyller warned about reading too much into the gene expression analysis because of the small sample size (n=29). The analysis found, though, that the TGF-B3 isoform was negatively associated with reduced expression of two B-cell genes (TNFRSF13C and CXCR5).

Wyller suggested that TGF-B3 may be altering the effect that cortisol – the master immune regulator – has on B-cell genes in ME/CFS. If TGF-B and cortisol combine to smack B-cell genes in ME/CFS, Wyller suggests that could translate into problems reining in Epstein-Barr virus (EBV) – a common trigger in ME/CFS. Wyller’s earlier gene expression study, in fact, suggested that B-cell problems could be the key to the EBV problems seen in ME/CFS. Now Wyller suggests that these B-cell problems could result from a complex interaction between TGF-B and cortisol.

Wyller’s going to check out that interaction in a study which will determine how effectively the B-cells in ME/CFS patients respond to EBV in the presence of neuroendocrine hormones. If cortisol or other neuroendocrine hormones impair the ability of B-cells to whack EBV in ME/CFS, Wyller may have uncovered one reason why mononucleosis is such a common trigger for ME/CFS.

Mold Connection?

Wyller’s focus on the research literature apparently precluded him from exploring another TGF-B angle. Mold has become a hot if little studied topic in ME/CFS. For over a decade, mold doctor Ritchie Shoemaker has asserted that elevated TGF-B levels play a major role in mold related illnesses. Instead of B-cells, though, Shoemaker ties TGF-B issues to T cell problems and reduced blood flow in the capillaries, which translate into reduced oxygen uptake and problems with producing energy in the mitochondria – a key theme in ME/CFS.

Shoemaker, interestingly, asserts those blood flow and immune problems mirror what is happening in sepsis. In fact, Shoemaker believes that the chronic inflammatory response syndrome (CIRS) he sees in his patients is a chronic form of sepsis. Over ten years ago ME/CFS specialist Dr. David Bell proposed a chronic form of sepsis exists in ME/CFS as well.

“In this monograph I would like to explore the concept of neuro-immune fatigue as a metabolic illness resulting from a series of events beginning with an infection, toxic exposure or neurologic injury.” Dr. David Bell, 2007

This is one of a series of blogs highlighting hypotheses mostly written by doctors or other professionals with ME/CFS, or in this case, doctors who have cared for them. The hypothesis examined in this case: Dr. Bell’s idea, produced in his monograph, “Cellular Hypoxia and Neuro-immune Fatigue”, that chronic fatigue syndrome (ME/CFS) could be a kind of “slow sepsis”.

Bell’s “Cellular Hypoxia” book was published in 2007, long before he was probably acquainted with Dr. Naviaux’s and others’ work and before the recent explosion of interest in cellular energy production in ME/CFS. Naviaux and others would probably smile, though, at Bell’s prediction that with ME/CFS and other diseases, “we may be witnessing the emergence of the next era of medicine: the diagnosis and treatment of cellular metabolic diseases”.

Sepsis is a life-threatening response to infection or trauma that can lead to tissue damage, organ failure, and death. In some ways, sepsis sounds similar to autoimmunity. For reasons the medical profession does not understand, sepsis begins when the immune system resets itself, stops fighting pathogens, and turns on the body.

The results are often devastating. The near complete body breakdown that results makes sepsis the most expensive disease hospitals treat. Forty percent of patients with severe sepsis do not survive.

Chronic Fatigue Syndrome (ME/CFS) – A Mild but Chronic State of Septic Shock?

ME/CFS is obviously not sepsis, but it does share some interesting characteristics. With his “cellular hypoxia” monograph published in 2007, Dr. David Bell suggested that people with ME/CFS may exist in a “mild, but chronic state of septic shock”. Bell came to this conclusion after finding that sepsis and ME/CFS produces what he believed is a similar kind of oxygen dysfunction. In sepsis and in ME/CFS, Dr. Bell notes that oxygen is actually abundant: it’s abundant in the air, the lungs and the blood of ME/CFS patients, but it’s just not getting taken up by the tissues.

Bell reports that in septic shock, the following events occur (note the last one):

a serious infection occurs which –

results in the production of cytokines which –

increases nitric oxide levels which then –

interfere with the production of cellular energy.

Bell noted that when nitric oxide blocks the flow of oxygen in severe septic shock, a patient can still die despite doctors giving him/her as much blood and oxygen as they need.

Bell suggests a similar process to sepsis occurs more gradually in ME/CFS. First, an initiating infection or toxic exposure triggers the immune system to produce pro-inflammatory cytokines and nitric oxide (NO). From there, NO increases peroxynitrite and superoxide (Martin Pall’s hypothesis), which causes oxidative stress and interferes with mitochondrial function.

Ultimately, the cell becomes hypoxic (oxygen-starved), and neuropathies and autoimmune and other problems develop.

The idea that impaired oxygen intake might be limiting energy production has gained some currency since Bell wrote his monograph. Vermoulen’s exercise studies suggest that impaired oxygen intake, not mitochondrial problems, is the key issue in energy generation. The early stages of Ron Davis’s collaboration with an San Jose State University bio-engineer suggest that the red blood cells may have difficulty getting to the tissues. Other researchers have found autoantibodies to receptors that open and close the blood vessels in a subset of ME/CFS patients.

Remarking that during sepsis, immune cells rely entirely on glycolysis to proliferate, Armstrong speculated, much as Bell did years earlier, that an infection or autoimmune process might have triggered a sepsis-like condition which lead to a state of chronic metabolic starvation.

A last tie to sepsis is an incidental one. Ron Davis and Ron Tompkins of the Open Medicine Foundation worked on sepsis together. Based on his work there, Davis has said ME/CFS could be a kind of atypical sepsis.

Two Vascular Diseases?

Blood vessel damage could play a central role in both sepsis and ME/CFS

Bell noted that a vasculopathy – inflammation of the blood vessels – was the first symptom (reddened cheeks) he noticed in ME/CFS. (That suggested to him that a parvovirus may have swept through his area.)

Cardiovascular issues could be central in both diseases. Perhaps the most interesting possible intersection between sepsis and ME/CFS occurs in the blood vessels – specifically the small blood vessels.

Recently an NIH Panel redefined sepsis as: “severe endothelial (blood vessel) dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure”; i.e. at its heart, sepsis is a small blood vessel disease caused by a pathogen attack – which is complicated by the immune storms that follow.

Sepsis has also been called a “malignant intravascular inflammation” characterized by excessive coagulation which blocks blood flows to the small blood vessels, reducing blood volume and lowering blood pressure.

Indeed, as Bell points out several times in his monograph, vascular issues show up again and again in ME/CFS, POTS, orthostatic intolerance and similar, related diseases.

Blood Pressure

Altered blood pressure is another sign of cardiovascular issues in both diseases. A sudden drop in blood pressure associated with an infection is an indication that sepsis has begun.

Blood pressure regulation problems are found in ME/CFS but anecdotal reports suggest that declines in blood pressure may be common as well. Bell writes that most, but not all, people with ME/CFS have low blood pressure – something that the medical profession has little interest in – unless you’re in the ICU. It’s ironic, Bell notes, that an ME/CFS patient with a blood pressure 75/40 will get little notice but put someone with that blood pressure in an intensive care unit and the sirens will go off.

Blood Volume

Low blood volume is common in sepsis and great efforts are made to increase it. Low blood volume, of course, is very common in ME/CFS as well. Sometimes blood volume is so low in ME/CFS as to stagger the mind, yet it’s received little attention.

Increasing blood volume can, of course, be helpful in ME/CFS, but is not as helpful as one would think, given the low blood volumes found. (Could microcirculatory problems be to blame?)

Blood Flows

In sepsis, blood flows in the microcirculation become so low as to damage the organs. That doesn’t appear to happen in ME/CFS, but even back in 2007, Bell was able to point out studies showing reduced blood flows to the brain and muscles was present.

Pathogen Damage

Sepsis was long thought to result from an overwhelming immune response to an infection but that’s no longer thought to be true. In 2010, however, that changed. The Working Group on Blood Systems Response to Sepsis, convened by the NIH’s National Heart Lung and Blood Institute (NHLBI), concluded that a cytokine cascade was not, as had been previously believed, the main culprit. The real issue in sepsis, they asserted, is damage to the blood vessels caused by an uncontrolled infection.

The damage is then exacerbated by many inflammatory factors (including Dr. Bell’s nitric oxide metabolites). A period of reduced immune activation or “immuno-paralysis” (caused by an overactive anti-inflammatory response/immune exhaustion) that follows then sets the stage for the reactivation of latent viruses such as EBV, HSV-1 and others which amplify the damage.

The immune response is still recognized to be important, particularly in the later stages of the disease, but the infections themselves and the damage they do mayt be the key factor.

That’s an intriguing finding given that the biggest factor in determining who gets ME/CFS and who doesn’t after an infection appears to be the severity of the initial infection. Could a severe infection kick off a low-grade, chronic type of sepsis in ME/CFS?

It’s possible that the difficulty NK cells – and probably T-cells – have in killing off pathogens in ME/CFS might just give those pathogens enough time to damage the blood vessels. Or, perhaps in other cases, an autoimmune process is sparked which does the same. (An autoimmune process appears to occur in some types of POTS).

Post-Sepsis Syndrome (PSS)

Interestingly, sepsis appears to be another potential trigger for chronic fatigue syndrome (ME/CFS). Post-sepsis syndrome (PSS) – a condition occurring in about 50% of sepsis survivors – indicates that surviving sepsis – perhaps like surviving the infection, injury or whatever that appears to trigger the onset of ME/CFS – is often not nearly the end of the story.

Extreme fatigue, problems with cognition, muscle and joint pains, insomnia and other sleep problems, that can last months or even years are common outcomes of sepsis. In fact, a sepsis trust has produced a support document specifically for post-sepsis patients experiencing “chronic fatigue“.

The medical profession has been content thus far to simply to document the extent of PSS – with little attempt to understand or treat it. The causes of the fatigue and chronic pain in PSS are completely unknown. This is despite the fact that several studies have made clear that PSS is a significant and enduring problem: statistics suggest that about 250,000 people a year come down with PSS.

The disease is clearly pathophysiological, but the only help The Sepsis Alliance could provide for the many chronically ill survivors was to get emotional and psychological support (counseling, cognitive behavioral therapy or neuropsychiatric assessment) or physical therapies.

Treatment

Sepsis is also confusing to treat. The first line of defense is a hearty dose of antivirals, fluid support, etc. From there it gets trickier. People with sepsis may have a pro-inflammatory phase followed by immune suppression (or both may be occurring at the same time). (Could ME/CFS be a kind of drawn-out sepsis with a longer pro-inflammatory phase followed by immune exhaustion?)

Researchers and doctors focused on reducing pro-inflammatory responses, but drug trials targeting the pro-inflammatory response have been ineffective. Now, researchers are targeting immune checkpoints in hopes of unleashing the power of the innate immune system.

Conclusion

Dr. David Bell

Chronic fatigue syndrome (ME/CFS) is not sepsis but the two diseases do share some intriguing characteristics. Both sepsis and ME/CFS often start with an infection; oxygen delivery to the tissues appears to be a problem; blood pressure, blood volume and blood flows are affected, and sepsis often results in a syndrome that symptomatically looks very much like ME/CFS.

As Roberts points out what’s happening in the very, very complex disease known as sepsis is still unclear. Whether or not the new drugs being developed for sepsis will play a role in ME/CFS is, of course, unknown as well. Drugs being developed to turn off the anti-inflammatory response are intriguing given the state of “immune exhaustion” that some studies have found in ME/CFS. If ME/CFS does turn out to be a kind of “slow sepsis” it will be a good idea to keep an eye on the developments there.

It seems logical that the ME/CFS community should begin to share knowledge and resource with the sepsis organizations such as International Sepsis Forum (ISF), Global Sepsis Alliance and Sepsis Trust and Post Sepsis Syndrome patients. The curative challenges ahead are monumental, involving complex pathways which have yet to be researched, and will no doubt result in individualized treatments.

Maureen Hanson has been making waves. An ace molecular plant biologist prior to entering the chronic fatigue syndrome (ME/CFS) field, Hanson has worked on mitochondrial and gene studies in plants dating back decades. Now, with her son ill from ME/CFS, she’s turned her talents to this field, and has made a difference in a hurry.

Last year Hanson was awarded a smaller NIH grant (R21) to do preliminary work assessing the energy production in ME/CFS patients’ immune cells using the Seahorse XF Analyzer. In this blog we take a closer look at the work underway.

A Breakthrough Technology

It’s safe to say that the Seahorse machine is changing how researchers do research. In the mid-2000s the Seahorse folks introduced something new to the medical world called “extracellular flux (XF)” technology. A monolayer of cells is placed in a very small, 10 ml sensor chamber and then stimulated. Every few seconds a sensor placed 200 microns above the cell monolayer takes a measurement. Where past techniques required hours to assess oxygen metabolism, the Seahorse can do it in minutes.

This technology allows researchers to determine the energy consumption of cells by analyzing changes in oxygen and acid levels occurring in the media outside of them. The amount of oxygen present indicates how much energy is being produced through glycolysis and by the mitochondria.

The ability to place energy stimulating or inhibiting or other drugs in the sensor chamber brings the possibilities of the Seahorse machine to an entirely new level. If the inability to produce energy turns out to be a key factor in ME/CFS, the Seahorse machine’s ability to test how drugs and other substances effect the energy production of cells could be a big boon indeed

Agilent, the company that produces the Seahorse machine, reports the machine has been used in over 250 studies. HIV researchers, for instance, recently used the machine to determine the effectiveness of the immune response in HIV patients. It turns out that in order to meet a threat, many of our immune cells undergo a huge metabolic shift as they get transformed from a resting to an active state. That shift coincides with large increases in glycolysis in particular.

A similar approach is being used in chronic fatigue syndrome (ME/CFS). Tomas’ recent Seahorse study suggested that ME/CFS patients’ immune cells (PBMC’s (T, B and NK cells, monocytes))are having severe problems producing energy. Tomas’ study opened up an important possibility but it was limited by its inability to determine which cells were having problems.

Hanson is taking the next step in assessing immune functioning in ME/CFS with her R21 NIH grant. That grant gave her the funds to assess the energy production of individual immune cells separately (T, B and NK cells). (Isabel Barao is also examining energy production in NK cells).

Each of these cell types has been potentially implicated in ME/CFS. The T-cell problems Derya Unutmaz of Jackson Labs saw are what attracted him to ME/CFS, and Mark Davis of Stanford recently found signs of unusual clonal expansion in ME/CFS patients’ T-cells. The success some ME/CFS patients have with Rituximab suggests B-cell issues are present, and the problems ME/CFS patients’ natural killer cells have with killing have been known for decades.

T-cells are a particularly good subject because springing into action to kill other cells or to produce clones of themselves to fight invaders requires enormous amounts of energy. If energy production is flawed in ME/CFS, it’s probably going to show up in patients’ immune cells.

Glycolysis OK

Metabolomic studies suggest glycolysis might be inhibited in ME/CFS, but at the OMF’s Stanford Symposium Hanson stated that she hasn’t found impaired glycolysis. When glucose was given to the immune cells to stimulate their glycolytic processes, the cells were able to use it, but their respiratory capacity (oxidative phosphorylation) was blunted.

In another study, which the SMCI helped to fund, Hanson’s Metabolon metabolomics study found lower glucose levels (a surprise) as well as differences in fat and lipid metabolism (i.e. energy production), and in the sphingolipids that play a big role in Naviaux’s findings.

Hanson noted that low glucose levels are not a good sign, either. Low glucose levels have been associated with increased cortisol responses (possibly leading to exhaustion) and inflammation. Plus they may be able to mess with a person’s endurance.

The last sport anyone with ME/CFS is going to engage in is an endurance race. That might make sense given that athletes with lower glucose levels tend to do worse in endurance sports. Overall Hanson’s metabolite findings suggest increased inflammation and reduced recovery from metabolic stress are part and parcel of ME/CFS. Metabolic stress, of course, is exactly what she’s measuring in her Seahorse study.

Hanson’s finding of normal glycolysis in ME/CFS patients’ T-cells mirrors the findings of Tomas’ recent Seahorse study. However, Hanson’s early findings are suggesting that, at least in the immune cells, the mitochondria are the issue.

Hanson has found that ME/CFS patients’ T-cells use less of their “respiratory capacity” when provoked than do healthy controls’ cells. If I’m reading this right, the capacity to produce energy is there, but it’s not being used. The next step is to determine if the T-cells, when they become activated, can produce enough energy to be effective. If Dr. Hanson finds they’re not up to the task of producing adequate energy, she said, “they may also be unable to effectively respond to an immune challenge.”

Lethargic T-cells could have major implications for the immune system, as T-cells are important in just about every immune system activity. At least four different kinds of T-cells exist: T-helper cells activate B and NK cells, T-killer cells destroy virally infected and cancerous cells, T-memory cells alert the immune system to danger, and T-regulatory cells help keep the immune system humming. Small studies suggest that cytotoxic or killer T-cells have the same problems with killing infected cells that NK cells do.

Whether or not something in ME/CFS patients’ blood is essentially putting their cells to sleep is one of the more fascinating questions facing this field. Several researchers including Ron Davis of the Open Medicine Foundation and Fluge and Mella in Norway believe something in the blood is doing just that. Energy production issues in ME/CFS patients’ cells that have been isolated from the blood suggest that something may be wrong with the cells themselves. It’s possible, therefore, that problems may lie in both the blood and the cells.

Since the Seahorse machine allows researchers to insert different substances in the medium the cells are bathed in, I asked Dr. Hanson if she could use the machine to determine the effects ME/CFS patients’ blood may be having on their immune cells.

Dr. Hanson replied that the Seahorse machine could determine if something in ME/CFS patients’ serum affects mitochondrial function in immune cells from healthy people, but the Seahorse technology would not be able to tease out what factors in the serum are responsible.

The Seahorse requires large samples of difficult to obtain immune cells. T-cells are relatively easy to obtain; B and NK cells – not so much. Getting Maureen Hanson the resources she needs to do her work is where the Simmaron Research Foundation comes in: it’s supplying the cells she needs to do her work. Dr. Hanson stated that, “We are grateful to Simmaron Research for supporting the collection of additional samples from which individual cell types— such as B and NK cells—can be purified for analysis of glycolysis and oxidative phosphorylation”.

Next up, Dr Hanson will analyze the cellular energetics of those NK and B cells. Despite the Rituximab failure, B-cells are still of great interest in chronic fatigue syndrome (ME/CFS). It’s still possible, for instance, that the drug works for a significant subset of patients. Plus B-cells are heavily involved in autoimmunity. Dr. Light has proposed that energy depleted B-cells may increase the risk of an autoimmune process beginning.

The desire to examine NK cells is obvious. Reduced NK cell cytotoxicity is a hallmark of ME/CFS, and reduced cytotoxicity of T-cells appears to be present as well. Could that poor killing power be caused by the most basic of all problems – the inability to generate enough energy? Given the high energy requirements of activated immune cells, that’s a distinct possibility. Dr. Hanson’s work will take us closer than any other yet to answering that most fundamental of all questions.

Over the past five years or so, Rituximab has been the great hope for the ME/CFS community. The anecdotal stories of dramatic recoveries were beyond enticing. A successful trial could ultimately have led to the first FDA-approved drug for ME/CFS and relief for many, a huge shift in how the disease is viewed, and surely more research funding.

That unfortunately is not to be. At a talk in Norway on Nov 21st, Dr. Mella revealed that the Rituximab trial that many laid their hopes on has failed. We don’t know and won’t know the details of the failure until the paper is published next year, and Drs. Fluge and Mella talk more about the study. Dr. Mella said they provided the result so that ME/CFS patients won’t try the drug on their own.

The Norwegian trial was never by itself going to lead to FDA approval for Rituximab’s use in ME/CFS. The trial was large and rigorous enough, though, to ensure that, if successful, another trial which could lead to FDA approval would follow. The trial’s rigor had equally negative consequences; it’s hard to imagine in this funding-hampered disease that anyone is going to fund a large Rituximab trial in the future.

The main finding of the Norwegian Rituximab trial was negative but Rituximab’s ,may role in ME/CFS may not be at an end.

Rituximab may never be an FDA-approved drug for the general ME/CFS population, but its role with ME/CFS may not be over, and smaller, targeted trials are still a possibility. From the beginning, Fluge and Mella recognized the possibility of a trial failure and had a backup plan in case it failed:

However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an immunological, rituximab-responsive disease.

Efforts to find biomarkers that identify the responders will be critical and are already underway. David Patrick of Canada reported on his use of microarrays to try and tease out which ME/CFS patients might respond to Rituximab at the 2016 IACFS/ME Conference. Nancy Klimas suggested that the Rituximab sera could very well hold the key to Rituximab’s future with ME/CFS. If autoantibodies are present in the Rituximab responders’ sera, they could be used to screen patients for future trials. She questioned whether the autoantibody patterns she’s seen in her studies might be predictive.

We know that some people with ME/CFS do respond very well to Rituximab. We’ll know more about them and the next steps Fluge and Mella will take with the drug and their other studies in early 2018.

The Rituximab Saga

The Rituximab saga began in 2004 when two oncologists noticed that Rituximab – a B-cell depleting drug often used in cancer – not only cured one of their patient’s cancer but eliminated their chronic fatigue syndrome (ME/CFS) as well. After two more ME/CFS patients responded similarly, they began their work on ME/CFS in earnest.

Several small case studies or trials ensued, all of which produced excellent results. The first one – called a preliminary case series in 2009 – reported on the three ME/CFS patients who’d improved on Rituximab. The second – a 2011 double-blinded, placebo-controlled 12 month trial of 30 patients – found Rituximab produced “major or moderate” results in 2/3rds of the participants.

The third, a 2015 open-label (the patients knew they were getting Rituximab) study, which involved giving the participants doses over a longer period of time, achieved similar results. The SF-36 scores of the major responders – about 50% of the study participants – suggested that they might be back to near normal. Not only did the trial succeed, but the trial suggested that the relapses dogging the patients from the first study could be prevented by continuing to take the drug.

The 152 person, double-blinded, placebo controlled trial that eventually resulted was spread across five hospitals in Norway. The trial had a rocky start with the Norwegian government pulling its support, but ultimately patient advocacy and patient support prevailed. The trial began in 2015 and wrapped up on time in September of this year.

Why the Trial Failed

We won’t know why the trial failed or how many people the drug worked for until the paper is published in the first half of next year but speculation is rampant.

Was “Failure”Always the Most Likely Outcome (?) – My probably minority opinion is that “failure” may have always been the most likely outcome of the study given the heterogeneity this community displays every day on Forums, Facebook and elsewhere on the internet. It may be too much to ask for many drug trials aimed at the entire ME/CFS community to succeed.

It’s important to note that Rituximab may still have a role to play in ME/CFS – just not as a drug for everyone. The key question now is how many people actually did respond to it. If a substantial number did, and a biomarker to identify them can be identified, the Rituximab trial will not go down as a failure at all.

Patient Bias? – Inadvertent patient bias – a possibility Fluge and Mella considered as the trial started – is probably the best candidate at this point. It could be that the smaller early studies inadvertently plucked out a more receptive set of patients. Once more patients were added to the mix, the effect disappeared. This is not an uncommon result in large Phase III drug trials:

“However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo).” Fluge and Mella

Placebo Effect? – Jorgen Jelstad put forth the intriguing idea that a high placebo effect could have doomed the drug. A similar situation appears to have doomed the Synergy trial. The Synergy compound actually did quite well but the placebo effect – possibly due to patients’ excitement about the treatment – was so strong that it was impossible to show clear separation between the effects of the drug and the placebo. Given the excitement around Rituximab, it’s possible that a similar situation has prevailed.

Endpoint – Not Disease? – It’s also possible that ME/CFS is not a single disease, but represents an endpoint or condition that can be reached in any number of different ways. Both Gulf War Illness and Lyme disease, after all, symptomatically appear to be the same as chronic fatigue syndrome but studies suggest that the three diseases are probably quite different biologically.

If different pathways exist to the same symptomatic or even cellular endpoints, then different treatment pathways will be needed. Alzheimer’s is possibly an excellent example of a complex endpoint – not a single disease – which will need a variety of approaches to resolve. Dale Bredesen MD believes that hundreds of millions of dollars and hundreds of prospective drugs have failed to make a significant dent in Alzheimer’s because the disease has been misidentified. Dale Bredesen’s studies suggest that an approach which assesses and treats a wide range of factors may actually work quite well in Alzheimer’s.

Drug Trial Failures Not Uncommon in Medicine

The ME/CFS and FM communities have recently, unfortunately, been getting acquainted with the fact that disappointments in drug trials are more common than successes. Rituximab had two small, but good, Phase II trials and seemed likely to succeed, but surprises in medical research, as Ron Davis has pointed out so many times, are common.

The next step will be determining who did respond to Rituximab and why

Jelstad’s interesting blog “The ME Rituximab Trial is Negative” (translated by Google into English) noted that Rituximab also failed in lupus despite the fact that it seemed hand-made for a B-cell associated disease. In fact, researchers were so shocked at the failure of the first large Rituximab lupus study that they immediately started another one – which subsequently bombed as well. (Despite all that, Rituximab can still work in lupus and is used in patients who haven’t responded to other treatments. )

Closer to home, two major Phase III fibromyalgia trials, one involving 10,000 patients, failed over the past year. As with ME/CFS and Rituximab, their Phase II trials had produced stellar results. Likewise, Wyller’s Clonidine trial seemed set up to reduce the “arousal” that seems manifest in this disease. Not only did the trial fail, but the drug actually made Wyller’s young ME/CFS patients worse. Medicine is full of surprises. It’s unrealistic to assume that ME/CFS won’t fall prey to some of them.

Cautionary Findings?

The result is disappointing but it’s perhaps not entirely surprising. Rumors from doctors using the drug in the U.S. on ME/CFS suggested the success rates might be lower than hoped for. If I’m reading them right, the immune B-cell studies in ME/CFS which sought to identify the issue Rituximab has addressed haven’t exactly been sterling successes.

Fluge and Mella proposed that long-lived autoantibodies or some other “slow alteration in the immune function governed by B-cells” could be causing ME/CFS. That idea was buttressed by a study finding increased rates of B-cell lymphoma in elderly ME/CFS patients.

When a German study found significantly reduced levels of muscarinic and B-adrenergic antibodies in Rituximab responders, the way forward seemed clear. Rituximab’s B-cell depleting properties were preventing B-cells from producing autoantibodies that were affecting blood flows and other processes.

The study possibly provided a cautionary note, however, when only 30% of the ME/CFS patients not given Rituximab (n=268) displayed the antibodies – a far smaller percentage than had responded in the early Rituximab trials. If those antibodies were what Rituximab was affecting – which was certainly not clear – many patients simply didn’t have them.

Meanwhile, studies that had focused on the B-cells in ME/CFS didn’t seem encouraging. Several studies prior to the Rituximab finding had not shown consistent B-cell differences between ME/CFS patients and healthy controls. A more recent found mostly modest alterations in B-cells in ME/CFS patients. Bradley’s conclusion that ME/CFS patients exhibited a “subtle tendency to autoimmunity” didn’t seem to jive with the idea that ME/CFS is a B-cell mediated autoimmune disorder”. Another study which found some B-cell abnormalities was unclear what their functional impact might be. A 2013 study simply found no differences in the B-cells of ME/CFS patients and controls.

Finally, researchers have had trouble figuring out what Rituximab was doing when it did work. Lunde’s 2016 study of ME/CFS patients receiving Rituximab found no difference in several immune measures (serum BAFF, T-Lymphocytes, T-cell activation) and just slight (but significant) reductions in immunoglobulin levels.

There’s certainly more to know about B-cells in ME/CFS – the Solve ME/CFS Initiative’s (SMCI) is funding a small study of B-cell energetics – but if B-cells are causing ME/CFS, they haven’t been giving up their secrets easily.

Enormous Impact

While the Rituximab trial failed in its main objective – to provide a drug for ME/CFS patients – there’s no denying that its impact has been enormous. Two highly creative researchers, Oystein Fluge and Olav Mella, have entered the field and say they intend to remain. Their wide-ranging efforts have and are touching on everything from autoantibodies to blood vessel functioning to metabolomics to exercise.

They and the Norwegian ME/CFS community put together the largest non-CBT/GET trial ever in ME/CFS, produced one of the largest biobanks, and created collaborations with researchers in Europe and the U.S. It proved that ME/CFS patients and their supporters from across the world will respond (Dr. Maria Gerpe reported that over 90 days, 5000 donors from more than 49 different countries contributed to the study). The Rituximab saga has provided a jolt of energy across the entire ME/CFS community.

Fluge and Mella and their supporters did the seemingly impossible: put on a large and expensive ME/CFS drug trial in a small country

Plus, the trial was not just about Rituximab. Several other studies baked into the study will add to our understanding of ME/CFS. A study examining endothelial function and skin microcirculation should tell us about blood flow issues – very possibly a key issue in ME/CFS. Their two- day exercise test should validate the highly unusual decline seen in the ability of ME/CFS patients to produce energy after exercise. Their gastrointestinal functioning test should, likewise, tell us about gut functioning in this disease.

Plus, Fluge and Mella are continuing with their cyclophosphamide trial. Cyclophosphamide has some real advantages over Rituximab. While Rituximab selectively targets B-cells, a more broadly based immune drug like cyclophosphamide may be more effective than Rituximab and has the decided benefit of being much, much cheaper. The drug is being tested in several hospitals across Norway.

Fluge and Mella have also published studies indicating breakdowns in energy production and the effects of cytokines on ME/CFS. Jorgen Jelstad pointed out that Katrina Lien’s multi-center Norwegian study is examining lactic acid production in ME/CFS. RItuximab’s early success prompted researchers to examine B-cells and autoantibodies more closely. Maureen Hanson is working with Norwegian researchers to assess the effectiveness of fecal transplants. None of this work would have been possible if Rituximab had not come to the fore.

The Rituximab saga showed that there’s no need to look to the U.S. for potential breakthroughs in this disease. Activists in smaller countries should be encouraged. Norway put the U.S. to shame in its ability to put together and fund the largest non-behavioral ME/CFS treatment trial ever. The Rituximab saga has shown that an active community and dedicated researchers in small countries can make a major impact on this disease.

We’ll know more about the next steps with Rituximab and Fluge and Mella’s work in 2018.

The Clinical Trials Picture

The loss of Rituximab puts renewed focus on Hemispherx Biopharma’s Ampligen – the other major drug possibility for ME/CFS.

Nancy Klimas at the Institute for Neuro-immune studies feels she has treatments to test now. Klimas has been chafing against federal restrictions that make it difficult to get ME/CFS clinical trials funded for years now. Neither the Research Centers grant nor, advocates take note, the Program Announcements for the ME/CFS SEP grant review panel, allow for the submission of clinical trial proposals. That means Dr. Klimas has go to rheumatology review panels to try and get her ME/CFS clinical trials funded.

Dr. Klimas reports that she’s received private funding for a phase I exploratory trial for women to start in Jan/Feb of next year and has raised half the money needed for a men’s study to hopefully begin shortly after that. (More on those later.)

Is Chronic Lyme Disease (CLD) actually Lyme disease? That’s one of the questions asked during the Simmaron Research Foundation’s Patient Day in September.

It was a full room in beautiful Incline Village sitting on the northern shore of Lake Tahoe in Nevada. Emily Taylor of SMCI came up from LA, Gunnar took time off from medical school. Maureen Hanson and Mady Hornig flew over from the East Coast; Dr. Konstance Knox from the Midwest. The locals included Anita Patton, Courtney Miller, Eric Johnson, and, of course, there was Dr. Peterson.

Why some people remain ill after being treated for Lyme disease is a vexing question

Why some people who have been treated for Lyme disease remain ill is a knotty question, and it has pertinence for chronic fatigue syndrome (ME/CFS). Both in Lyme disease and chronic fatigue syndrome (ME/CFS) many people become and then remain ill after an infection. Why that happens is a mystery.

Some people think that chronic Lyme disease is simply another subset of chronic fatigue syndrome; that the Borrelia burgdorfii infection which ticked off chronic Lyme disease is no different from the herpesvirus or enteroviral or other infection that just happened to send ME/CFS patients’ systems into a tailspin. The idea is that it’s not the infection, it’s the fact that an infection occurred. That’s what the Dubbo and other studies which have shown that ME/CFS can be triggered by a large of number of pathogens suggest.

Others believe that the Borrelia infection is still there, deeply hidden, but grinding away in the chronically ill.

No one knows, but the idea that different pathogens are causing similar issues in ME/CFS and Lyme is belied by a study which found significantly different proteins in the cerebral spinal fluid of ME/CFS and Lyme disease.

Dr. Konstance Knox believes the two diseases may, in fact, be very different. In her Simmaron Patient Day presentation, she suggests a pathogen may be present in chronically ill Lyme disease patients but not the Borrelia bacteria; she believes that a tick-borne virus called the Powassan Deer Tick virus, which at its worst is fully as dangerous as Borrelia or more, may be doing its work.

The Powassan Deer Tick Virus

The Powassan Tick-borne virus was first isolated from a person from Powassan, Canada in 1958. (Powassan, like Lyme, Connecticut, is another small town that just happened to get stuck with the name of a disease.) The Powassan virus is a Flavivirus related to such nasties as Zika, Dengue, West Nile Virus, and tick-borne encephalitis virus (TBEV). All these viruses can cause brain swelling (encephalitis).

The scariest thing about the Powassan virus is how quickly it can be transmitted. Because the Borrelia bacteria that causes Lyme is carried in the stomach of a tick, the tick has to feed for quite a while before the bacteria actually makes into humans. Because the Powassan virus, on the other hand, is carried in the saliva of the deer tick, it takes a mere 15 minutes or so for it to jump from a feeding tick into your bloodstream. A Powassan infected tick can jump on, feed for a bit – transmit the virus – and then jump off, without you ever knowing it. Since ticks are so small and POWV transmission so rapid, few patients with Powassan encephalitis recall their tick bites.

Most cases of Powassan virus infection are mild but at its worst a Powassan virus infection rivals Lyme disease in its severity

Most people infected with Powassan Virus (POWV) experience flu-like symptoms such as headache, sore throat, drowsiness and disorientation. If the infection spreads to the brain, the virus can cause everything from lethargy, high fevers, vomiting, respiratory problems and difficulty speaking to paralysis, seizures, coma and even death.

Powassan-triggered encephalitis is accompanied by the infiltration of lymphocytes and monocytes into the brain and the widespread destruction of neurons in the motor areas of the brainstem (affecting movement), the cerebellum, basal ganglia (potentially affecting movement again) and the thalamus. MRI’s pick up only non-specific abnormalities and thus are not diagnostic but suggest that brainstem may be particularly effected.

Studies on Powassan infections are rare but some suggest that no less than fifty percent of Powassan survivors may be left with permanent neurological problems including partial paralysis, headaches, memory impairment and/or paralysis of the eye muscles.

A 2015 paper presenting eight verified cases of neuroinvasive Powassan virus infection in New England bore this out. Two of the patients died, four fairly quickly recovered and two exhibited from medium to long-term problems. One 21 year old man who entered the hospital with vomiting, fever and confusion was given methylprednisolone and IVIG. He improved over time and left the hospital alert, oriented, and “speaking in short sentences”. He was unable to return to work for seven months. Fifteen months later, a 52 year old man still had persistent headaches as well as problems with motor functioning and coordination.

Because surveillance of the Powassan virus has been poor, it’s difficult to estimate its true incidence in humans. Luckily, far more ticks carry the Borrelia bacteria (20-50% of ticks in endemic areas) than carry the Powassan virus (1-10%). Unluckily, the Powassan virus appears to be spreading.

After Powassan virus caused the sudden death of a Massachusetts woman, a tick surveillance program found from 0-16% of ticks in a given area carried the virus. A Canadian survey suggested that 3% of residents of Ontario province in Canada had been exposed to the virus. These surveys suggest far more people have been exposed to the virus than suspected. Most undoubtedly experienced symptoms similar to those of a mild cold. Others who were more seriously affected probably never got tested for Powassan.

Much of what we know about the Powassan virus comes from study of a closely related virus in the Europe and Asia called Tick-borne encephalitis virus which causes thousands of neurological illnesses every year. Studies on the Powassan were almost non-existent until around 2011 when the research started picking up. Powassan virus is considered a “rare but severe neuroinvasive disease“.

Could Chronic Lyme Disease Caused by the Powassan Virus?

Dr. Konstance Knox, Coppe Lab

Simmaron Scientific Board member and collaborator, Konnie Knox has been leading a recent surge in research publications on the Powassan virus. Her recent survey of the Ixoides scapularis ticks known to carry Lyme disease and Powassan virus in Wisconsin found that 5% carried the Powassan virus. Rather ominously half of the ticks carrying Lyme disease also carried the Powassan virus.

With Lyme disease fairly common in Wisconsin (@ 187 cases/100,000) Knox’s finding strongly suggested that Powassan infections were being under-reported in Wisconsin. (If Knox’s findings are validated, then Powassan virus infections probably occur on the order of at 90 cases per 100,000 in Wisconsin, or as much as 5400 cases per year.)

Serologic evidence of POWV infection was present in 10% of the patients and confirmed in 3% of them by other testing. Almost half of the patients with an acute Borrelia infection were infected with the Powassan virus. When the patients with a validated Powassan infection were tested, 87% were also found to be infected with Lyme disease. None, fortunately, had signs of a neuroinvasive disease.

The fact that 10% of Lyme patients come down with Chronic Lyme Disease and, Knox’s findings suggest that about 10% of patients with Lyme disease may also be infected with the Powassan Virus, is of course, more than intriguing.

Could chronic Lyme disease or ME/CFS patients be suffering from a unusual, untreated infection? Knox’s present research into ME/CFS patients could help answer that question. Knox will be testing several hundred ME/CFS patients for evidence of Lyme Disease, Powassan virus, and other tick and insect-borne diseases.

Lyme Disease Or ?

Konstance Knox who owns a diagnostic laboratory, noted that Lyme testing has improved and that good Lyme testing is not impossible. (She liked the CDC protocol which calls for a two-step testing process.) She’s confident in the results from her lab which uses machine testing rather than subjective human testing to assess the test results.

She noted that one of the biggest problems with Lyme diagnosis is getting tested too early. Because it takes about four weeks for the Lyme immune factors to show up in the blood, the tests aren’t accurate until you’ve been infected for about a month.

The Lyme diagnosis question, of course, is a big one. Get it wrong, as the story of one ME/CFS patient in the audience indicated, and you could be in for years of expensive treatments which leave you worse off. After a diagnosis based on neurological and non-specific symptoms, a CD 57 test, and a negative Western blot test from Igenex, this patient had been on and off antibiotics for about five years. Talking to her later she said she’d improved tremendously on antibiotics at times, but the treatment ultimately failed and left her worse off than ever. (She suspected that the anti-inflammatory effects of the antibiotics had temporarily helped.)

She would be in the chronic Lyme disease category except for the fact that she never have had Lyme disease in the first place. In fact, her symptoms didn’t really fit. She’d marveled at other “Lyme patients” who were able to exercise. Despite the fact that she’d visited a clinic that treated complex, chronic diseases, she didn’t know that her main symptom – post-exertional malaise – was the defining characteristic of ME/CFS until she visited an ME/CFS clinic last year.

Knox suggested that a lot of putative “Lyme” patients may not be Lyme patients at all. She’s found, for instance, a very low incidence of Lyme disease in Dr. Peterson’s patients, many of whom probably hail from the Western United States. She did, however, find evidence of a tick borne virus in about 11% of a 200 patient sample.

Conclusion

People who still suffer from the symptoms of Lyme disease after being appropriately treated for it are a medical mystery. Some doctors believe the Lyme bacteria is still present. Others believe that the Lyme infection may have triggered an ME/CFS-like condition. Simmaron Research Foundation Board member and collaborator, Dr. Konstance Knox, believes some people with chronic Lyme disease may be suffering from an unidentified Powassan virus infection transmitted by the same tick.

Powassan virus is a poorly studied virus that can be quickly transmitted by ticks. While most people probably pass off the virus quickly, a neuroinvasive infection can cause serious symptoms including paralysis, stroke, coma and even death.

Dr. Konstance Knox’s studies suggest that Powassan virus is often present in ticks harboring the Borrelia bacteria that causes Lyme disease, and that about 10% of Lyme disease patients have been exposed to the virus. That’s an intriguing finding given that about 10% of Lyme patients come down with chronic Lyme disease.

An entire state goes “ME”. That’s never happened before. Courtney Miller of Simmaron, Emily Taylor of the Solve ME/CFS Initiative, MEAction and the USAWG worked together to enroll the entire Nevada Congressional delegation to put its total support behind increased funding for ME/CFS.

This is notable not just because it’s never been done before, but because for years patients in Northern Nevada sought help from Congressman Amodei and Senator Heller with little success. This is the story of persistence and success. Hopefully we’ll be seeing more of this as the attitude towards chronic fatigue syndrome (ME/CFS) shifts.

Courtney and Bob Miller have been advocating for ME/CFS for many years, but when Emily came up with the rather audacious plan to get the entire state delegation on board, they were energized.

Persistence Works

After the elections in Nevada, Courtney Miller and a group of patients recommitted to taking a sustained approach. Not willing to let the decisions of the past stop them, Courtney met the staff of the Congressman and her Senators after the Women’s March in Washington. At that point Amodei got interested in ways to improve the federal agencies’ response to the disease.

Then in a Spring Town Hall meeting Courtney got up to the microphone and publicly asked Sen. Catherine Cortez Masto for her support. With that Sen. Catherine Cortez Masto’s staff got involved and she joined the effort.

Next during the first Lobby Day in ten years (thanks to SolveME/CFS and MEAction) some patients from Nevada met with Cong. Amodei himself and the Senators. Emily, Sonya, Courtney and others created a draft delegation letter (see attachment). In June Courtney returned to DC and visited the office of every member of the NV delegation. This time the response was enthusiastic; Congressman Amodei agreed to sponsor the letter and set a deadline.

Finally, last week Emily from Solve ME/CFS Initiative and Courtney hit the phones, Anita – the go to person for patients in Incline Village – urged Nevada patients to send emails, and Emily set up a Solve ME/CFS Nevada action alert so that more Nevadans could urge their reps to sign on. (The SMCI has an automated and easy way to contact our reps.) By Friday, the entire Nevada delegation agreed to push Director Collins for more funding.

The State Delegation Game

The game now is to get entire state delegations to sign on. Obviously it’s going to be harder with bigger states (although in conversation Emily mentioned the “big apple”). Besides everything else, getting everyone in a state delegation on board is a great game to play. It sends a powerful message when an entire delegation comes together like that.

I asked Emily what was next.

Next steps are to repeat the process with our strong leads in other states and build up to bigger state delegations. A state delegation letter means a single letter sent from every member of congress (senators and representatives) from that state.

We are truly fortunate to have so many strong advocates leading the charge and dedicated partners coming together with this strategy. I am really excited about this tactic because it effectively leverages the relationships we have built in the past year (particularly in the May ME/CFS Advocacy week actions) and it is a strategy that lends itself to our community’s strengths.

Another key advantage of this approach is the consistent pressure it will apply. State delegation letters take time to organize, so a new state delegation letter every couple of months keeps a constant awareness and pressure to act on ME/CFS. I think this is a good way to avoid the “push-crash” cycle we’ve seen in past advocacy efforts.

As for a comment to add – I’d like to send out a special thanks to Courtney and Bob Miller, Anita Patton, Annette Whittemore, and the many Nevadans who took action to make this campaign a success. This was a long-term, team effort. It’s always toughest to be first! Hopefully, we’ll have many more state delegation letters to come. Emily Taylor – SMCI

Who’s next? Now that Nevada has proven it can be done, who’s next? If you want to your state to be the next to go all “ME” email Emily Taylor at ETaylor@solvecfs.org and let her know.

Most people with chronic fatigues syndrome (ME/CFS) and fibromyalgia (FM) know the consequences of poor sleep – the fatigue and pain, the difficulty concentrating, the irritability and more. Sleep is when our body rejuvenates itself; no sleep – no rejuvenation. Given how important sleep is to our health, it’s no surprise that poor sleep is the first symptom many ME/CFS and FM doctors focus on in.

Poor sleep is often the first symptoms ME/CFS/FM practitioners focus on

The effects of poor sleep go beyond just feeling bad, though. It turns out that poor sleep can have significant effects on our immune system – effects, interestingly, which are similar to what’s been found in the immune systems of people with ME/CFS and FM. There’s no evidence yet that ME/CFS and FM are sleep disorders – that the problems ME/CFS and FM patients face are caused by poor sleep – but depriving the body of sleep can cause one immunologically, at least, look like someone with these diseases.

Irwin begins his review on sleep and immunology by noting the “explosion” in our understanding of the role sleep plays in health over the past decade. First, Irwin demolishes the idea that sleep studies are effective in diagnosing insomnia or sleep disturbances other than sleep apnea. Far more effective than a one or two-night sleep study is a home based sleep actigraph “study” which estimates sleep patterns and circadian rhythms over time and is coupled with a sleep diary.

In fact, Irwin points out that the diagnosis of insomnia in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is based solely on patient reports of difficulties going to sleep, maintaining sleep, having non-restorative sleep (common in ME/CFS) and problems with daytime functioning (fatigue, falling asleep, need to nap). (Problems with daytime functioning are actually required for an insomnia diagnosis).

The Immune System and Sleep

The immune system is vast and incredibly complex and has it’s own extensive set of regulatory factors, but it itself is regulated by two other systems, the HPA axis and the sympathetic nervous system. Both are involved in the stress response and both are effected in ME/CFS and FM. One – the HPA axis – is blunted in ME/CFS while the other – the sympathetic nervous system – is over-activated.

Poor sleep, it turns out activates both system. The HPA axis is generally thought to be blunted not activated in the morning in ME/CFS patients but the sympathetic nervous system (SNS), on the other hand, is whirring away at night (when it should be relaxing) in both FM and ME/CFS. (Having our “fight or flight” system acting up at night is probably not the best recipe for sleep.) ‘

One study likened sleeping in fibromaylgia to a stress test (!)

Sympathetic nervous system activation, in fact, was the only factor in one Australian study which explained the poor sleep in ME/CFS. The authors of a recent FM/autonomic nervous system study went so far as to suggest that going to sleep with FM was equivalent to undergoing a stress test (!). Heart rates, muscle sympathetic nervous activation, and other evidence of an activated sympathetic nervous system response made sleep anything but restful for FM patients. In fact, the authors proposed sleep problems could be a heart of fibromyalgia.

Many questions have involved the roles pathogens play in ME/CFS and FM. That’s intriguing given the almost universally poor sleep found in the disorders and role recent studies indicate that sleep plays priming the immune systems pump to fight off invaders. During sleep pathogen fighting immune cells move to the lymph nodes where they search for evidence of pathogens. If pathogens are present those immune cells mount a furious (and metabolically expensive) immune response.

Metabolism is a big issue in ME/CFS right now but guess what? Poor sleep also appears to interfere with producing the metabolic reserves our immune cells need to fight off infections.

We often think of inflammation in negative terms but the pro-inflammatory cytokines our immune cells produce are necessary to fight off invaders. Reductions of a key pro-inflammatory cytokine called IL-6 during poor sleep hampers our immune system’s ability to destroy pathogens.

Getting your circadian rhythms (sleep and wake times) out of whack isn’t doing you any good either. Having insomnia or altered sleep patterns (very late bedtimes) appears to cause deficits in two hormones (growth hormone (GH) and prolactin) produced during early sleep which enhance T-cell activity and promote pathogen defense. That suggests that anyone with an altered circadian rhythm (i.e. late bedtimes) might want to do their best to get to bed earlier.

While pro-inflammatory cytokine production at night primes the immune system to fight off pathogens, the day time is a different story. Chronic sleep deprivation is associated increased daytime levels of several immune and endothelial factors ((IL-6, TNF) and endothelial markers (E-selectin, sICAM-1) that are associated with chronic inflammation.

One study found IL-6 levels actually became flipped in sleep deprived people; they were low at night (thereby hampering their pathogen fighting ability) and high during the day (adding to inflammation).

Pathogens love it when you get a night of poor sleep

The situation may be even worse if a sleep deprived person is fighting off an infection. One study found skyrocketing levels of damaging pro-inflammatory cytokines when sleep deprived people were given a toxin (LPS) associated with infections. Those damaging cytokines did not show up in healthy people. That suggested that besides the infection they probably weren’t doing too well at fighting off, sleep-deprived people now had inflammation to deal with.

As it often happens, women seem to have gotten the short end of the stick with immune issues and it’s no different with sleep. Women appear to be more susceptible than men to inflammation that occurs as the result of poor sleep; it’s women, not men, who show elevations of pro-inflammatory cytokines the day after getting less than eight hours of sleep. (Men show elevations of pro-inflammatory cytokines after getting less than six hours of sleep).

Many people with ME/CFS/FM get too little sleep but sleeping more than normal, it turns out, is not such a great idea either. People sleeping much longer than normal tend to show the same kinds of elevations of pro-inflammatory cytokines as do people who get too little sleep.

The C-reactive Protein Sleep, ME/CFS and Fibromyalgia Connection

CRP is associated with a variety of inflammatory states resulting from infection, cancer and stress. Increased levels of the inflammatory marker, C-reactive protein (CRP), are increasingly being associated with sleep disturbance.

The CRP – sleep connection is intriguing given Jarred Younger’s preliminary finding of increased C-reactive protein (CRP) levels in a subset of ME/CFS patients, and a recent finding in increased CRP in FM.

Those findings might not be so surprising. Ten days or so of partial sleep deprivation in healthy controls caused “robust” increases in CRP levels. In fact, the CRP-poor sleep connection is so robust that simply scoring above five on the Pittsburg Sleep Quality Index (PSQI >5) strongly suggests that your CRP levels are elevated. A huge nurses study (n=10,908) found that non-restorative sleep – probably the most common sleep issue in ME/CFS/FM – was associated with increased CRP levels even in these healthy individuals.

The early or innate immune response has long been thought to play a special role in ME/CFS. This immune response involving NK cells, neutrophils, macrophages, dendritic cells and others constitutes the immune system’s first defense against pathogens. Immune cells involved in the early immune response called monocytes/macrophages also play a key role in producing chronic inflammation.

NK cell activity hits a low during sleep but then begins to rise. That the rise is blunted in people with poor sleep probably comes as no surprise to NK cell challenged ME/CFS patients.

ME/CFS isn’t the only disease associated with NK cell problems; depression is as well and having poor sleep increases your risk of being depressed twofold. Plus, for reasons that are not understood, poor sleep appears to trigger stress and depression initiated reductions in NK cell activity; i.e. if you’re having poor sleep and are under considerable stress or are depressed – it’s likely that your NK cells are punking out when it’s time to defend the body from invaders.

We know that having a chronic illness increases ones chances of becoming depressed markedly, but so does poor sleep. In fact, Irwin reports that having insomnia for over a year increases your risk of becoming depressed 14-fold. That finding is leading some of the more progressive psychologists to focus on preventing or ameliorating sleep problems.

Sleep disturbance also induces a shift toward a type-2 immune response often seen in ME/CFS and in allergic and autoimmune diseases. Just one poor night’s sleep the night before a person is given a vaccine is enough markedly reduce the effectiveness of that vaccine. A study showing just how frighteningly malleable the immune system can be to stressors such as poor sleep found that a 50% reduction in the effectiveness of an influenza vaccine persisted over a year. Even after three doses of the vaccine and a booster shot were given adults getting fewer than six hours of sleep a night still received less protection from a hepatitis B vaccination than normal.

The common cold, of course, is no joke to some people with chronic fatigue syndrome (ME/CFS) and FM when it lingers and lingers. Studies suggest that poor and fragmented sleep – which is, of course, common in ME/CFS/FM – significantly increases one’s susceptibility to the common cold. If you’re catching a lot of colds or if they linger and linger, poor sleep could be one reason why.

What To Do?

OK – so poor sleep places a big hurt on our immune system’s effectiveness. What to do about it? No studies, unfortunately, have examined the effect of sleep drugs on immune factors so we’re not going to go there.

A little stress reduction could play dividends…

Several studies have, however, assessed the efficacy of stress reduction therapies. Dr. Irwin notes reports that practices such as cognitive behavioral therapy, Tai Chia and yoga which tamp down sympathetic nervous system hyper-arousal can help improve immune functioning. Tai chi has even been found to improve vaccine effectiveness and reduce inflammation.

Other studies point to the ability of mindfulness based meditations and/or yoga to reduce the cytokine levels and pro-inflammatory gene expression caused by poor sleep. One remarkable study showed a 50% reduction in CRP levels in insomnia patients after a year of cognitive behavioral therapy.

There’s been a great deal of controversy and confusion surrounding ME/CFS — even whether it is an actual disease. Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.” Mark Davis

There’s nothing like a high-profile study from a major university. For one thing it can get you publication in one of the most prestigious journals around. The journal the Montoya/Mark Davis study was published in, The Proceedings of the National Academy of the Sciences, is the official publication of the National Academy of Sciences. Its website gets about 21 million hits a month; this study is going to get around.

The study examined the levels of a very large number of cytokines (n=51) in the blood of a very large number of patients and healthy controls (ME/CFS=186; healthy controls= 388). Age, sex, race and something called “nonspecific binding” were accounted for.

This was one study we really didn’t want to fail

One of the biggest ME/CFS immune studies ever undertaken, done at a top University, this was a study that we dearly didn’t want to fail. This is the kind of study likely to be labeled “definitive”. It was on scale with the Columbia cytokine study, where co-authors Ian Lipkin and Mady Hornig analyzed 51 cytokines in 298 patients and 348 healthy controls. If the results of these two hallmark studies were discordant, it would have had negative consequences to any immune interpretation of this disease.

Smaller cytokine studies in ME/CFS have a history of inconsistency, making the similarities in these two studies important.

Results

The first news was not good. The levels of only two cytokines, TGF-Î (elevated) and resistin (lowered) were different in the patients compared with controls. Displaying an unusual level of consistency for ME/CFS, TGF-B has now been found elevated in about six out of the ten studies it’s been tested in.

TGF-B has not received a lot of attention possibly because researchers are not sure what it means. An anti-inflammatory cytokine that can have pro-inflammatory properties, the authors noted that TGF-B is elevated in a number of dissimilar conditions (cancer, liver disease, inflammatory bowel diseases among others). The authors suggested TGF-B may have pro-inflammatory properties in ME/CFS; instead of tamping down inflammation, they proposed it may be “may be a major factor in promoting relentless inflammation.”

Big Finding

“Remarkably, 17 cytokines were associated with severity in ME/CFS patients.” The study authors

Dr. Montoya got the money for the study and conceived it, and Mark Davis advised him on it, was the senior author of the paper, and tested the samples in his lab.

Davis has won a slew of prizes (The Paul Ehrlich Prize, The Gairdner Foundation Prize, The King Faisal Prize, the General Motors Alfred P. Sloan Prize) and is on the Open Medicine Foundation’s Scientific Board. He’s a big deal in the immune world.

Montoya and Davis hit the bulls-eye when they threw severity into the mix

I talked to Davis a couple of days after the study’s publication. I asked him about the main results; those 17 cytokines that predicted severity – was that a lot? It’s an important question. A couple of cytokines popping out might mean that the immune system is involved but is not a major player – time to look someplace else. A lot of cytokines showing up, on the other hand, suggests the immune system may very well be it in ME/CFS – time to dig deeper.

Was 17 cytokines a lot? Even in the staid language of scientific journals the surprise at the size of the effect came through: “Remarkably”, the paper said, “17 cytokines were associated with severity in ME/CFS patients.”

When I asked Davis if it was really a lot, I heard him take a deep breath: “it’s a lot – really a lot” – he said. Getting a third of the immune factors to show up suggests massive immune involvement. Davis – who is involved in constructing immune signatures for different diseases and health – said everything he’s seen about this disease suggests autoimmunity. That’s a particularly meaningful statement from such a well-known immunologist. He’s getting to know ME/CFS pretty well: Montoya’s study is the biggest study his public lab has run.

(Mark Davis has two labs – his private research lab and a larger, more public lab he set up to run many more samples at a time. That lab, which got a big federal grant, was designed to bring the same kind of rigor he uses in his private lab to bigger studies. Researchers like Dr. Montoya can bring their samples to the lab and have the lab test them. That’s what happened in this study)

A Different Kind of Disease?

Mark Davis thinks ME/CFS is probably an autoimmune disease. You don’t see the kind of overt cytokine increases in ME/CFS that are seen in autoimmune diseases like rheumatoid arthritis and lupus. This study, in fact, suggested that cytokines were not increased in the patient group as a whole relative to healthy controls.

Adding severity to the mix, however, suggested that cytokines were heavily involved in this disease. Mark Davis said he’d never seen a disease with mostly normal cytokine levels but which presented such clear indications that cytokines affected symptoms. He suggested that other diseases like Alzheimer’s might display similar patterns if researchers started looking for them.

In an interview with Miriam Tucker, Dr. Montoya echoed the unusual nature of the disease: he simply called the immune activation in ME/CFS – as he has for some time now – a different kind of inflammation.

“Inflammation is much more complicated than two imperfect old measures [sed rate and C-reactive protein]. We’re showing an inflammation that has not been seen before.” Jose Montoya

Three Options?

But what could be causing this bizarre pattern? Higher cytokine levels could certainly explain the more severe fatigue in some ME/CFS patients, but how do the low or normal cytokine levels explain the fatigue in the more moderately fatigued patients? They do have ME/CFS after all; even if they are less ill than the severely ill, they are still enormously fatigued but their cytokine levels aren’t elevated at all. In fact the cytokine levels are lower than normal in some of them. Three options have been suggested.

(1) Loss of Immune Control In the Severely Ill

One possibility the paper presented is that the healthier patients with lower levels of pro-inflammatory cytokines are able to control them to some extent. Their immune systems are grinding away but they’re keeping – probably at some cost – the pro-inflammatory elements under control. The control mechanisms of the sicker patients, though, have collapsed – they’re bearing the burden of unremitting cytokine activity.

(2) A Localized Infection

In conversation Mark Davis suggested that a localized infection could also be causing the immune system to react – not with the huge increases in cytokines seen in systemic inflammatory or autoimmune diseases but with small, harder to detect ones. He’s not the first to suggest that. A couple of years ago Michael Van Elzakker proposed exactly that scenario for ME/CFS.

ME/CFS may be a different kind of inflammatory disorder

Van Elzakker proposed that localized infections – probably involving the vagus nerve – were causing small, hard to detect elevations of cytokines. Meanwhile the infections were playing havoc with the vagus nerve’s ability to communicate sensory and immune information to the brain.

I asked Van Elzakker about the study. He believes the cytokines this study picked up in ME/CFS are probably spillovers from an infection or injury. He cited Robert Dantzer, an important figure in sickness behavior research and pyschoneuroimmunology, who in a (2014) Trends in Neurosciences review, The Neuroimmune Basis of Fatigue agreed that with regard to fatigue:

“The measurement of circulating concentrations of cytokines represents the main limitation of the present studies on fatigue and inflammation. Given that cytokines are autocrine and paracrine communication factors, their circulating levels have little functional value and represent mostly spillover from the site of cytokine production and action.“

Given how profoundly limited many people with ME/CFS are – Van Elzakker believes these localized infections probably exist in the neuroimmune nerves such as the vagus or trigeminal nerves.

There’s another possibility. Gordon Broderick’s modeling work in chronic fatigue syndrome (ME/CFS) suggests that context may be king in the immune system. During a recent phone call Broderick described the co-expression study he did that found a changed immune landscape in ME/CFS. Cytokines such as IL-1b, 2, 4, IFN-Î³, TNF-Î± and IL-10 had larger than expected impacts in ME/CFS patients relative to healthy controls while other cytokines had less impact.

If Broderick’s right, none of the cytokines found in Montoya’s study need to be elevated to have a significant effect – they simply have to be embedded in a dysregulated immune network.

Leptin is Back

This is the second time leptin has shown up in a Stanford study, and the researchers suggested that it might be the keeping the chronic inflammatory state in ME/CFS intact. It turns out that adipokines – cytokines secreted by fat cells – like leptin may be able to trigger neuroinflammation. They’re also found in higher levels in women and may be a particularly important trigger in female dominated inflammatory diseases such as multiple sclerosis.

Duration

In contrast to the Lipkin/Hornig and another study, this study found little evidence of increased cytokine levels earlier in the disease or decreased levels later in the disease. The small numbers of short duration patients (n=30) in the study, however, could have prevented any findings from reaching statistical significance. Interestingly, the study did not find that disease duration was correlated with severity; i.e. patients who had been ill longer were not necessarily worse off.

Diagnostic Test?

Mark Davis suggested the findings might prove the basis for a diagnostic test but in conversation indicated we’re far from one right now. Much more study is needed.

The diagnostic test problem is greater in the low to moderately ill patients who have similar cytokine levels to healthy controls. How to devise a test to distinguish them from the healthy controls with similar cytokine levels is the big question.

Montoya reported that his team was working on a five-cytokine panel that would require a doctor first classifying each patient by severity. If Montoya can devise specific cytokine signatures for each level of severity, a test might be feasible, but it’s clearly going to be a complex undertaking.

Big Study (Too Big?)

Montoya rather courageously put a lot money into an area of research – cytokine analyses – that have had their problems in ME/CFS. As the Lipkin/Hornig study and this study showed, when it comes to immune studies size is definitely better.

While it is possible that this study had more controls than needed, at least Montoya didn’t err on the other side – too few patients; that might have been fatal to this study. Mark Davis thought that given all the noise in the data, that a smaller study might not have found much.

Don’t Think Too Much: the Zen of ME/CFS

In a kind of Zen-like statement Mark Davis cautioned about “thinking too much” about this disease at this point. Davis wasn’t suggesting not inquiring about the disease, but not coming to conclusions about it. We’re not there yet. We’re more in a space of creative inquiry than anything else.

Mark Davis warned against coming to conclusions; more views of ME/CFS is what we really need

Things got even more zen-like when Davis referred to a famous series of paintings called Thirty-six views of Mt. Fuji to underscore where we are with ME/CFS right now. The celebrated series by Japanese artist Hokusai shows Mt Fuji from different perspectives including from at dawn, from a window in a house, from behind a huge wave, etc., etc.

To Davis, ME/CFS is like Mt Fuji; we need to look at it from a lot more angles to fully understand it. The most important thing we can do now is to test, test, test and let the data guide us.

This study may demonstrate that more than anything. It, after all, had four highly unusual results – very little evidence of immune dysregulation compared to healthy controls; massive evidence (17 cytokines!) on the other hand, that the immune system is effecting severity, a substantial number (on the other, other hand) of individuals with low or low-normal cytokine levels, and finally two cytokines with abnormal levels which didn’t have anything to do with severity at all.

This study, then, boosted interest in the immune system in ME/CFS, while raising a lot of questions about it at the same time. A lot of work – a lot of exploratory work – remains to be done to figure this puzzle box of a disease out.

In fact, exploration is largely carrying the day in ME/CFS research. Montoya got hundreds of samples, tested them as widely as possible, analyzed them a bit and then stood back. Ditto with the Ian Lipkin/Mady Hornig immune study, the metabolomics studies from Armstrong and Naviaux, (Naviaux, however, has a hypothesis), Ron Davis and the Open Medicine Foundation with their severe ME/CFS Big Data study, and Avindra Nath and his deep Intramural NIH study. They’re all exploring.

Mark Davis’ talk at Open Medicine Symposium on Saturday should be a good one. NINDS Director Dr. Koroshetz talked up Davis’s exciting findings in the recent NIH Telebriefing, and Ron Davis thinks they may be even more significant than this paper. If you’re at the Symposium you can ask him about his work or Mt Fuji or just say hello and thanks.

Treatment

This study is a major legitimizer and a big spur for more immune studies – particularly big immune studies. One thing it doesn’t present are clear treatment options. When I asked Mark Davis about treatment options, he was unwilling to commit to any line of treatment based on the results. He agreed that basing treatment options off of this study would be like shooting fish in a barrel.

That doesn’t mean the study won’t help on the treatment end. The severity results, after all, scream inflammation. That suggests anti-inflammatories might very well help. Ron Davis noted that many immune affecting drugs are under development right now which might be useful for ME/CFS in the future. We simply need more study to assess which targets might be best.

If Gordon Broderick’s right, though, it may take more than knowing a cytokine’s levels to find the right target. Broderick’s working on complicated models that incorporate the effects hormone levels, in particular sex hormone levels, have on immune factors in ME/CFS. Broderick believes he’ll be able to devise a treatment approach that pushes the immune system one way and then another in order to nudge it back to a stable and healthy state.

Fatigue or Functioning?

While the multi-dimensional fatigue index used to assess fatigue has been validated as a good measure of fatigue across many diseases, one wonders if a functionality scale might have worked better. Fatigue is what ME/CFS is known for, but it’s real impact is on functioning. It’s possible to be very fatigued and still work, or to be pacing effectively – and not doing much work – and be less fatigued.

The MFI worked well in this study and past ME/CFS studies have used it, but one wonders if a scale that tracks functionality – how much activity one is actually doing – might have been more effective at tracking severity.

Slow Progress

Montoya has been given much (reportedly $8 million donation in 2008) and promised much, but the ME/CFS work has been slow. He’s a toxoplasmosis expert, possibly the top expert in the country, and he’s been pouring out toxoplasma studies – fourteen since 2015 – but the work in ME/CFS has gone much slower. Since 2009 he’s been the senior or lead author on just four ME/CFS studies – two of which involved the valganciclovir trial and predated the opening of his ME/CFS center.

This latest study was the most important one – it will undoubtedly help the field – but one hopes that with this monster study out of the way Montoya will be able to move faster on his other ones. His current research projects page lists ten studies. Two involve the Zinns who, unable to publish their work at Stanford, exited to work with Lenny Jason. Those studies are surely not extant.

The eight others, though, involve brain imaging, neuroendocrine, gene expression, cardiovascular, immune and pathogen studies. In a telephone conversation Mark Davis referred to some scintillating results he and Montoya are working on using the immune data Montoya gathered. Let’s hope we’ll see those results and more from Montoya’s Chronic Fatigue Initiative in the not too distant future.

Conclusion

This study, as did the Lipkin/Hornig study, suggested you have to approach ME/CFS differently than other diseases to be successful.

One of the things that emerged from this study is that ME/CFS really, really is different and woe to any researcher who assumes that it’s not. The regular rules of the road do not apply – you can’t just measure cytokine levels and expect to get anything. You have to dig deeper, and what this study and the large Lipkin/Hornig study before it demonstrated was that if you do dig deeper, you might stumble on something extraordinary.

The study’s excellent pedigree – it’s size, the lab it took place in and the journal it was published in – guarantees it will get noticed and that’s a good thing. The most important aspect of the study may be the legitimization it confers on the illness. Hopefully the study will introduce new researchers intrigued by what could be a new type of inflammatory disorder to the field. While more work is needed, the study also points to possible future effective treatment options. Lastly, the study indicates, as did the Lipkin/Hornig study, that bigger really is much, much better in ME/CFS research. Hopefully funders will take a cue from these large studies, and support the bigger and more definitive studies this disease needs to move forward.

A Big, Deep Fishing Expedition

The NIH’s Intramural Study on ME/CFS now underway is almost certainly the most comprehensive chronic fatigue syndrome (ME/CFS) study ever done. In fact, it may be one of the more multi-faceted studies done in any disease. It’s breadth is astonishing. Besides the blood, urine, fecal matter and saliva gathered, participants will spend a night in a metabolic chamber, get their brains scanned, have their their immune systems transplanted into mice, and their neurons grown in a petri dish. After years of patient advocacy – at least in this one study – ME/CFS has abruptly transitioned from being one of the poorest studied diseases of all to getting an array of cutting-edge technologies thrown at it.

The NIH is casting a wide, wide net in its intramural ME/CFS study

Featuring top researchers at the NIH’s big research hospital its results are guaranteed to get noticed. This one study won’t solve ME/CFS – no one study can do that – but it could and really should provide dramatic new insights into it, and, most importantly, provide the foundation for years and years of study into it. Nath, for instance, recently suggested the study could produce the bio-signature we’ve been seeking for years.

The study is basically a huge fishing expedition, an anomaly for an institution known for its strict adherence to hypothesis testing. The NIH is looking (and building data) just about everywhere in patients.

We probably have NIH Director Francis Collins to thank for that. Collins has more control and discretion over the intramural site than any other part of the NIH and it shows. Collins got this study started before the NIH allocated money for the research centers. He wanted and got Avindra Nath – a highly prestigious researcher specializing in neuro-infectious diseases – to lead it and he got the NIH to bring out its fishing poles and fish.

Round One: The NIH’s “Deep Phenotyping Exercise”

Not only is the breadth of the study unusual, but the rigor with which it’s being run is unmatched. The first part of the study (participants come in for two rounds of testing) is partially being done to ensure that only one kind of patient participates. This is an important point since the ME/CFS disease population is very heterogeneous and mounting studies are identifying distinct subgroups.

In order to capture post-infectious ME/CFS patients, the study requires participants to have a sudden flu-like onset that’s been documented in a doctor’s files. After taking questionnaire after questionnaire, a complete review of a patient’s medical records are being made by a panel of ME/CFS experts. Dr. Dan Peterson noted that one patient’s file ran to 191 pages (he said read every one). Dr. Peterson, longtime expert ME/CFS clinician and Simmaron Scientific Advisor, is reviewing patient selection for the NIH Intramural study.

Even the ME/CFS doctors reviewing the patient records have been taken aback at times with the strictness of the study. Dr. Peterson relayed one incident where Brian Walitt’s questioning of whether a patient should be included in the study raised eyebrows. (Walitt is the clinical lead investigator. Wallitt promptly dug into the Canadian Consensus Criteria to show the exact criteria the patient didn’t meet.)

Dr. Peterson noted that the reviewers have debated how “sudden” a sudden onset needs to be for someone to be included in the study. Does a patient have to remember the exact date they became ill or is something more general sufficient?

Another interesting twist concerns the rigor with which prospective patients have been tested. ME/CFS doctors that do more testing that others are more likely to find something that could kick a patient out of the study. That same patient coming from an ME/CFS doctor that doesn’t do a lot of testing might get into the study.

The first part of the study is apparently an attempt to level the playing field. Test after test after test is being done during the nine days a) to gather data and b) to ensure that nothing other than ME/CFS (and specified co-morbid diseases) is going on in these patients. At least in these early stages anything that looks off is being investigated. The NIH is calling the visit a “deep phenotyping” exercise.

An ME/CFS Patient Reports: Brian Vastag on Round One of the Intramural Study

It was fitting that Brian Vastag be one of the first ME/CFS patients to go through the first part of the study. He did after all, play a role in getting it started.

Francis Collins, the Director of the NIH stops by for a visit. Vastag pushed for more ME/CFS funding and asked for ME/CFS to be assigned to a single institute

Vastag used to work for the NIH; in fact, Vastag worked with John Burklow, Francis Collins’ right hand man for communications for years. Vastag also worked with the Journal of American Medical Association (JAMA), and then reported for the Washington Post on science and medical issues. He knows the NIH well and used his personal connection to Collins to lobby for more funding.

He got in the study the old-fashioned way – by emailing the study recruiter. In the months leading up to his stay, Vastag reported he had several conversations with the lead clinical investigator, Dr. Brian Wallitt, provided his medical records, was fully informed what he was in for and was provided several opportunities to bow out if he chose.

Thus far the reviews of Dr. Walitt from two people (Dr. Peterson, Vastag) participating with him have been positive. Dr. Peterson said he found him attentive and interested, and Vastag, who said he spent a lot of time with him, found him available and dedicated.

Vastag spent five or six hours relaying his medical history to Dr. Walitt and nine full days in the NIH hospital. The history, he said, was very detailed.

Some people have worried that the ME/CFS patients well enough to participate in the NIH’s intramural aren’t sick enough to get results. Brian Vastag is exhibit number one why that hopefully is not the case.

When Vastag got sick he got really sick. At one point, he was 98% bedbound. On his eighth or nineth doctor journey, Vastag saw neurologists and got checked out at a multiple sclerosis clinic. Now he’s probably moderately ill for an ME/CFS patient and has to limit his walking to about 2 blocks a day; e.g. Vastag cant work at all, and he’s functionally very limited.

My guess is that if you can only walk two blocks a day without getting whacked there is something seriously, seriously wrong with you. Ditto with work; if you can’t work without getting hammered you have something seriously wrong with you that should be discoverable.

Having moderately ill people (by ME/CFS standards) participate in a study may not get the sickest patients in the study but it also brings with it the bonus that researchers don’t have to worry about the confounding factors that severe deconditioning brings. If there’s something to find in the testing the NIH is doing it should be found in these patients.

Cutting-Edge Technology

“I can’t believe they are letting us do all this stuff”.

Brian Walitt, MD MPH

The NIH is after all, throwing a lot of new technology at this disease. Vastag was told the intramural researchers have the green light to do a deep exploration of this disease and to let the evidence take them where it will. They also have carte blanche to add to the study if the need arises.

Avindra Nath stops by. Vastag said Nath had a great sense of humor. (Photo by Beth Mazur)

The head of Clinical Neurology at the Intramural Center, Avindra (Avi) Nath, heads the study. Nath has co-authored hundreds of journal articles and is on the editorial board of several journals. His main research focus – on the effects of infection on the brain – couldn’t be better suited to ME/CFS.

His latest paper on the cerebral spinal fluid in the survivors of the Ebola epidemic is exactly the kind of post-infectious work he’s been tasked with doing in ME/CFS. His 2016 review of Ebola survivors highlighted the functional declines seen in those who survived the outbreak. The study also noted that joint and muscle pains were “persistent problems” in more than half the 200 plus survivors assessed.

“Tellingly, the survivors reported a functional decline when compared with before the EVD outbreak. In comparison with the household contacts, the survivors were more likely to report a decline in both overall health (70% vs 18%) and ability to work (70% vs 7%).”

Nath told Dr. Peterson, after Peterson’s NIH talk on epidemic presentations of ME/CFS, that the Incline Village outbreak was probably an infectious encephalitis type of outbreak but that the technology at the time wasn’t up to diagnosing it. Nath has also collaborated often with Dr. Ian Lipkin on infectious diseases, and we know Lipkin’s work in ME/CFS is refining our understanding of immunity in the disease. Nath’s 2015 review paper demonstrated that the HIV virus may be able to survive in reservoirs in the brain indefinitely.

Nath will oversee a huge amount of work and do some cutting-edge work of his own. Using a new technique developed in his lab, Nath will knock out the immune systems of transgenic mice and give them the immune systems of ME/CFS patients. He’ll also turn white blood cells from ME/CFS patients into “brains in a dish” neurons grown in the lab that Nath can then test. This technique, pioneered by Nath for other neurological diseases, can point highlight certain types of cellular problems.

A ton of data is being gathered in the first part of the study. Besides his half a day of questionnaires, Vastag had standard labs done, provided his spinal fluid, did a sleep study, got 3.4 billion white blood cells drawn for Nath’s experimental studies, had his blood drawn for the Sea horse (mitochondria/energy production) study, had an EMG done to rule out muscle myopathy, did a tilt table test( positive for POTS), an MRI, and gave samples for the metabolomics part of the study. Just about every “tissue” possible, from blood, to urine, to cheek swabs to cerebral spinal fluid was gathered.

Rebekah Feng is studying the mitochondria in ME/CFS

Some results may already be showing up. The Seahorse study results from just three patients were unusual enough that the intramural mitochondrial expert came down to Brian’s room and chatted with him.

Part II of the study will require a week’s stay and include an exercise test on a stationary bicycle, sleeping in a metabolic chamber, cognitive testing, and more blood and other tests.

The study’s only down-side appears to be its size and the time it is taking. Vastag reported that Nath expressed regret that the study was taking so long and told him that he was trying to speed things up. A couple of months ago, Vastag said he was the fourth patient to go through the study. At the NIH Telebriefing Nath said ten people have now gone through the first part of the study and one will start the second part at the end of July. Since the second part of the study was originally slated to begin in fall, it appears that Nath may indeed have speed things up.

Some researchers and doctors have expressed concern about the study’s forty-patient size, but Nath is convinced he can peel off any subsets with the patient group he has to work with.